Ageing

Only a matter of time

Want to live to 100? Inheriting the right genes helps

WHEN Sophie Tucker, a popular singer and vaudeville star, was asked the secret of her longevity, she replied “keep breathing”. New research suggests that the secret may actually be more complicated. It is a matter of having the right genes.

Annibale Puca, of the Howard Hughes Medical Institute in Boston, and his colleagues compared the genetic material of 137 sets of aged siblings to see if they routinely shared particular stretches of DNA. The results, just published in the Proceedings of the National Academy of Sciences, suggest that they might. Long-lived siblings frequently have a particular piece of chromosome 4 in common (ie, all the brothers and sisters involved inherited it from the same parent). That suggests this piece of chromosome carries a gene which, when present in a particular version, helps people to live to an exceptionally old age.

Dr Puca's study is the first to scan the entire genome for such data. Having found a region of interest, though, is only a start. First, the result needs to be confirmed. Linkage studies, as these sorts of investigation are known, have a habit of evaporating under scrutiny. Second, if it is confirmed, the gene (or, possibly, genes) involved must be identified. The draft of the human genome that is now available should make that easier than it would have been a few years ago, but the chromosomal region that Dr Puca has identified still contains several hundred genes that need to be examined.

Even so, mere confirmation would be a significant advance. Researchers have known for years that longevity runs in families, but they have debated how much that is due to genetic influences, and how much to a shared environment. Supporting evidence for a genetic contribution comes from experiments on fruit flies, mice, threadworms and yeast. These show that if such creatures inherit the right genes their lifespans can be extended dramatically. Furthermore, some human genes are already known to contribute in a small way to longevity, protecting against Alzheimer's disease and heart problems.

Theory also supports the idea that ageing is under genetic control. The “disposable soma” hypothesis suggests that length of life is a balance between the energetic investments that an individual makes in reproduction and in maintenance. However, as Thomas Kirkwood, one of the authors of this hypothesis, and a professor of medicine at the University of Newcastle-upon-Tyne, in England, points out, the hypothesis suggests that ageing is complex, and involves multiple genes—which is not what Dr Puca seems to have found.

Thomas Perls, a professor of medicine at Harvard Medical School, and one of the authors of the study, says the group has its own dose of healthy scepticism. Nevertheless, some of the authors of the study (including Dr Perls) are not so sceptical as to miss out on the opportunity to start their own company—Centagenetix—in order to pursue the matter. One thing in favour of there being only a few genes involved, observes Dr Perls, is the rarity of centenarians: only one in 10,000 people make it. If Centagenetix find longevity genes, he says the firm will patent them.

If a few crucial longevity genes are found, they would certainly be interesting. They could form the basis for research into the cellular pathways that are important to the ageing process. That would give clues about how to slow down ageing in the wider population. Dr Perls speculates that some kinds of disease-resistant genes may be involved—for example, genes that are better at repairing DNA, or genes for metabolic processes that produce rather fewer damaging, oxygen-rich free radicals.

That might explain why what looks to be a big genetic advantage is actually so rare in the population. According to the disposable soma hypothesis, individuals who make a large energetic investment in maintenance and the ability to fight disease may be compromising their ability to reproduce. This fits with a study Dr Kirkwood did on fertility, family size and lifespans in British aristocrats (for whom good genealogical records are available). Aristocrats with the longest lifespans had smaller families. Furthermore, work he has published in August's Nature Medicine suggests a mechanism. Women who have a highly reactive immune system might be better able to fight off infectious diseases but, conversely, be more likely to reject embryos in their wombs (with whom they share only half of their genes) as foreign objects.

If Centagenetix finds the hoped-for genes there is one other issue worth considering. If exceptional longevity is conveyed by only a few genes, these could be tested for in a relatively simple fashion. Some people would then know that their risk of dying young is far lower than average. These individuals would benefit more than the average person from their pensions and less from life insurance.

Life insurance works on the basis that individuals do not know their precise risks of dying. As Steven Haberman, a professor of actuarial science at City University, in London, points out, if somebody retiring at 60 knew that he was likely to live to be 110, barring accidents, he would not want to take out life insurance and subsidise the less long-lived in society. Buying an annuity, however, would give him an income for nearly half his life. So, if there is a precise genetic marker for longevity, insurance companies need to have the same information that an individual has—or they will go bust. Yet, according to Dr Haberman, companies selling annuities take no notice of the risk of their customers living much longer than average.

Dr Perls reckons that it will take about nine months to track down the crucial gene or genes, if it or they exist. In the meantime, Ms Tucker's advice still obtains: do not hold your breath.